To test whether the leukotriene antagonist ONO-1078 (pranlukast) prevents asthma exacerbations during reduction of high-dose inhaled corticosteroid, we conducted a randomized, double-blind, placebo-controlled study in 79 asthma patients requiring high doses (1,500 microg/d or more) of inhaled beclomethasone dipropionate (BDI) for clinical control (duration of asthma, 11.0 +/- 3.1 yr; duration of BDI treatment, 0.5 +/- 0.3 yr; FEV1 percentage of predicted, 80.7 +/- 2.0%). After a 2-wk run-in period, the doses of BDI were halved, while the patients were assigned to receive orally ONO-1078, 450 mg twice daily, or placebo. In the placebo group FEV1 decreased by 0.33 +/- 0.20 L after 6 wk (p < 0.001). Likewise, morning and evening PEF decreased by 46 +/- 7 L/min and 18 +/- 6 L/min, respectively. By contrast these variables were sustained above baseline in the ONO-1078 group. The number of daytime and nighttime asthma symptoms and the use of beta2-agonist increased in the placebo group, whereas they remained unchanged in the ONO-1078 group. In the placebo group concentrations of serum eosinophil cationic protein and exhaled nitric oxide increased (p = 0.007 and p = 0.025, respectively), compared with no change in the ONO-1078 group. Therefore, the leukotriene antagonist ONO-1078 prevents the asthma deterioration provoked by a 6-wk reduction of the dose of inhaled BDI into half.

OBJECTIVE -Serum triglyceride levels are important in the development of atherosclerosis. Although triglyceride levels are generally increased in the postprandial periods, the association between postprandial triglyceride (pTG) levels and atherosclerosis has not been investigated in diabetic patients. To investigate the role of pTG levels in atherosclerosis, we examined the correlation between pTG levels and carotid intimal-medial thickness (IMT).RESEARCH DESIGN AND METHODS -Carotid IMT was measured by ultrasonography in 61 patients with type 2 diabetes. Plasma glucose (PG), insulin, total cholesterol, triglycerides, and HDL cholesterol levels were measured after overnight fasting and 4 h after a meal.RESULTS -Carotid IMT of the patients with fasting hypertriglyceridemia was greater than that of the patients with normal fasting triglyceride (fTG) levels (0.85 ± 0.12 vs. 0.76 ± 0.14 mm; P = 0.02). The carotid IMT was increased in the patients with pTG levels Ͼ2.27 mmol/l. The normo-normo (NN) and normo-hyper (NH) groups consisted of patients with normal fTG levels but with pTG levels Ͻ2.27 and Ͼ2.27 mmol/l, respectively. Patients with both hypertriglyceridemia and pTG levels Ͼ2.27 mmol/l formed the hyper-hyper (HH) group. Carotid IMT was significantly increased in the NH (0.86 ± 0.13 mm) and HH (0.85 ± 0.12 mm) groups compared with the NN group (0.73 ± 0.13 mm; P Ͻ 0.01). Although postprandial PG, pTG, and fasting LDL cholesterol levels were all independently correlated with carotid IMT, pTG levels had the strongest statistical influence (P = 0.002).CONCLUSIONS -Postprandial hypertriglyceridemia despite normal fTG levels may be an independent risk factor for early atherosclerosis in type 2 diabetes.

To study the effect of adenosine 3',5'-cyclic monophosphate (cAMP) on respiratory ciliary activity, we measured ciliary beat frequency (CBF) of rabbit tracheal epithelium by a photoelectric method in response to cAMP analogues and agents that can increase endogenous cAMP production. Addition of 8-bromo-cAMP dose dependently enhanced CBF, with the maximal increase and the concentration necessary to produce a half-maximal response (KD) being 31.0 +/- 3.4% (SE) (P less than 0.001) and 3.2 +/- 1.5 x 10(-7) M, respectively. Other structurally dissimilar cAMP analogues dibutyryl cAMP and chlorophenylthio-cAMP likewise caused increases in CBF. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and the adenylate cyclase stimulator forskolin also augmented CBF in a dose-dependent fashion and were accompanied by the increases in intracellular concentrations of cAMP. Ciliary discoordination was not observed in any of the experiments. These results suggest that cAMP may accelerate mucociliary clearance through the activation of ciliary motility and that intracellular cAMP levels appear to be an important determinant for the lung mucociliary transport functions.

__________________________________________________ ___Mucous gland size and the amount of muscle in the bronchi were measured in 7 patients with typical chronic bronchitis, 4 patients with chronic bronchitis and attacks of wheezing (chronic asthmatic bronchitis), and 3 patients with classic spasmodic asthma. The patients with asthma had increased bronchial muscle, but the patients with chronic bronchitis did not. Three of the 4 patients with asthmatic bronchitis had increased muscle; such patients can therefore be recognized morphologically, and might account for a proportion of patients with bronchitis and unusual degrees of airways obstruction. Mucous gland size was increased in asthma when assessed by the Dunnill point count, but not by the Reid index.

Pressure-volume characteristics and morphologic changes were investigated in lungs of growing rats with streptozotocin-induced diabetes mellitus. Lung elastic recoil examined with quasi-static, air-filled pressure-volume curves showed no significant differences from that in control rats at all lung volumes. No alterations of surfactant properties as measured by a surface balance were observed. A 24% increase in the volume proportion of alveolar wall was found in the lungs from diabetic rats. There was an increase in the relative amounts of collagen, elastin, and basal laminae in the alveolar wall. There were more alveoli per unit volume in the diabetic animals (49.12 X 10(5)) than in the control animals (39.80 X 10(5)) (p less than 0.05) and there was an increase in the surface-to-volume ratio of the lungs of the diabetic rats.

The effect of alpha 1-proteinase inhibitor (alpha 1Pi) administration on the acute lung injury and subsequent fibrosis induced by bleomycin (BLM) was examined in hamsters. Pulmonary lesions were quantitatively reduced in alpha 1Pi-administered BLM-treated (BLM-alpha 1Pi) animals compared with animals treated by BLM alone (BLM-control) at both 7 days (acute stage) and 30 days (fibrotic stage) after BLM treatment. Analysis of intraalveolar cells from bronchoalveolar lavage (BAL) fluid revealed that neutrophils and lymphocytes were significantly decreased in the BLM-alpha 1Pi animals at 7 days after BLM treatment and that 30 days after BLM treatment macrophages as well as neutrophils and lymphocytes were remarkably decreased in the BLM-alpha 1Pi animals. The elastase activity in supernatants of BAL fluid during 7 days following BLM treatment was detected, but there was no difference between the two groups. In vitro studies on neutrophil responsiveness to stimulation of BAL fluid at 3 days after BLM treatment revealed noticeable chemotaxis and generation of superoxide anion of isolated neutrophils, but alpha 1Pi did not show any inhibitory effects on neutrophil responsiveness. We suggest that alpha 1Pi administration ameliorates pulmonary fibrosis preceded by acute lung injury induced by BLM treatment in hamsters and that the inhibitory effects of alpha 1Pi on lung injury may not be brought about by altered elastase activity, chemotaxis, or superoxide generation in neutrophils. Alternative mechanisms are discussed.

Excessive production of sputum is one of the major symptoms in patients with chronic airway diseases. Because endogenous prostaglandins may play a role in the regulation of airway secretions, blockade of cyclooxygenase pathway with indomethacin could decrease respiratory tract fluid and mucus by inhibiting Cl secretion and glandular secretion and by enhancing Na absorption across airway mucosa. To test this hypothesis, we studied the effect of inhaled indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, and bronchiectasis in a double-blind, placebo-controlled fashion. Patients who inhaled 2 ml of indomethacin (1.2 micrograms/ml) three times a day for 14 days showed a decrease in the amount of sputum, from 189 +/- 19 to 95 +/- 21 g/day (p less than 0.001) and an increase in the solid component of sputum without alterations in parameters of systemic inflammatory responses. Although pulmonary function remained unchanged, perceived dyspnea was improved so that Borg's ratio scale was decreased from 7.1 +/- 0.5 to 4.5 +/- 0.4 (p less than 0.01). Adverse effects, including hypotension and bronchoconstriction, were not observed. The reduction of sputum was accompanied by a significant decrease in the concentrations of prostaglandin (PG)E2, PGF2 alpha, thromboxane B2, and 6-oxo-PGF1 alpha in the sputum. Thus, indomethacin inhalation may be of value in reducing bronchorrhea sputum, probably through the inhibition of PG-dependent airway secretions.

We wished to determine whether adenosine, a purine nucleotide, modulates activity of respiratory cilia and, to this end, we studied cultured rabbit tracheal epithelium in response to adenosine and related substances in vitro. Ciliary beat frequency (CBF) as determined by a photoelectric method was depressed by adenosine (10(-3) M), the maximal decrease from the baseline value (965 +/- 29 beats/min, mean +/- SE) being 31.6 +/- 5.0% (p less than 0.001). The adenosine A2-receptor agonist N-ethylcarboxamide adenosine had only a small effect on ciliary activity, whereas other adenosine analogs elicited decreases in CBF in a dose-dependent fashion. The order of potency of cilia-inhibitory action was N-cyclohexyladenosine (an agonist for adenosine A1-receptor) greater than phenylisopropyladenosine greater than adenosine greater than N-ethylcarboxamide adenosine. Intracellular cyclic AMP (cAMP) levels were decreased by 10(-3) M adenosine from 39.2 +/- 6.5 to 25.3 +/- 4.8 pM/mg protein (p less than 0.05). The effect of adenosine on CBF was enhanced by dipyridamole, an adenosine uptake inhibitor, and by deoxycoformycin, an adenosine deaminase inhibitor. The adenosine-induced decreases in CBF and cAMP content were reversed by 8-phenyltheophylline, an adenosine receptor antagonist. These results suggest that there is an adenosine A1-receptor on rabbit tracheal epithelium that inhibits adenylate cyclase, which may result in the impairment of respiratory ciliary activity, and that adenosine-induced ciliary inhibition may be modulated by adenosine uptake and its catabolism by airway epithelial cells.